Chlorpropamide in Parkinson's Disease

disease includes the following observations, but their significance is not yet clear: (1) There is evidence of a connection between abnormal glucose tolerance and post' encephalitic Parkinson's disease (Gillhespy and Paton, i960; Terrana and Adragn^ 1951). McCowan, Harris and Mann (1926) give glucose tolerance curves for a group of patients with post-encephalitic Parkinsonism which are clearly diabetic in type. (2) Electrocoagulation in the basal ganglia in a diabetic with Parkinson's disease ameliorated both conditions (Gillingham, Watson, Donaldson and Naughton, 1960)(3) In 1958 a diabetic with Parkinson's disease showed improvement of both condi' tions when started on Tolbutamide (Gates and Hyman, 1958), and these authors late1 found that cases of Parkinson's disease without diabetes also improved. A subsequefl1 double-blind trial did not confirm this (Heller, Dejong and Magee, 1961). (4) Dresel and Lewy (1921) described lesions in the globus pallidus in four diabetic5 who died in diabetic coma. Bodechtel and Erbsloh (1958) agree that changes do occ^ in the globus pallidus in diabetes, but suggest that they are not specific for diabeteft and are found elsewhere in the brain.

(3) In 1958 a diabetic with Parkinson's disease showed improvement of both condi' tions when started on Tolbutamide (Gates and Hyman, 1958), and these authors late1 found that cases of Parkinson's disease without diabetes also improved. A subsequefl1 double-blind trial did not confirm this (Heller, Dejong and Magee, 1961).
(4) Dresel and Lewy (1921) described lesions in the globus pallidus in four diabetic5 who died in diabetic coma. Bodechtel and Erbsloh (1958) agree that changes do occ^ in the globus pallidus in diabetes, but suggest that they are not specific for diabeteft and are found elsewhere in the brain.
The present trial was not intended to throw any further light on the anomalies 0' glucose metabolism in Parkinson's disease, but was undertaken because there has s? far been no well-controlled trial of chlorpropamide in this condition. Chlorpropamide is a drug which can cause hypoglycaemia both in diabetic and non-diabetic subject5 which may be severe and prolonged if taken in too large a dose (Putelat, Bouhey> Lacroix and Veillet, 1962). This is a potential hazard to elderly arteriosclerotic patients and is one reason why the drug should not be used in Parkinson's disease unless its value is clear.

METHOD
The trial was double-blind. Eighteen volunteer patients from the neurologic^ clinic were assigned at random to two groups, A and B. Each patient was seen five times at 3-week intervals, and at each of the first four visits a bottle containing 21 tablets was issued. The patient was told that each bottle might contain the actu^1 drug or dummy tablets. In fact, group B received 100 mg. chlorpropamide daily the first 6 weeks, while group A received the dummy. This was in addition to an) previous medication, which was continued without change throughout the trial. Foj the final 6 weeks the groups were crossed over. At each visit the patient was assessed by one observer in three different ways: (1) The patient was asked whether he had noticed any improvement or worsening since starting the last lot of tablets.
(2) The time taken to perform each of sixteen actions in a standard way was measured' These actions included tests of manual dexterity and others involving trunk and H ^scles, and were based on movements common in everyday life to minimise the ettects of practice. The patients were asked each time to perform the test as rapidly Possible, and an attempt was made to keep the level of exhortation constant. The ' Sorter tests were done twice at each visit.

Tests
Open and close a safety pin. "?
Cork and uncork a bottle.
c-Fold a letter and put it in an envelope. "?
Unscrew and screw up a jar top.
e-Open a matchbox and strike a match.
J-Slice a block of plasticine. <?? Transfer food from one plate to another using a fork.
V Drink a glass of water. J-Put on a dressing-gown. ?* Walk a measured distance. P-Mount a step ten times. r^est of writing and drawing were given on a standard sheet for each hand in turn, he sheets were coded with random numbers and shuffled. Later the five consecutive ests for each patient were arranged in order of excellence and scored 1 (best) to 5 I Worst).
(3) Each limb was graded o (normal) to 5 (severely affected) for rigidity and tremor eParately. No attempt was made to assess trunk muscles. Rigidity was assessed by Passive movement at all joints of the limb, and the grade given was determined by the m^cles most affected.

RESULTS
1 ? Subjective impression. Each patient received the same treatment for two successive i^yeek periods and was then crossed over. The periods have been shown separately in able I} }n case there is a delayed effect due to chlorpropamide. In fact, as many Patlents felt better on the dummy as on chlorpropamide, and there did not appear to e any delayed improvement due to the latter. Timed tests. For individual patients at each visit a figure for the time taken to ^Plete the tests was required. Since the time taken by the different tests differed considerably the greater influence upon the average time of tests with longer duration was eliminated by using the log transformation of the time. Each patient acted as hiJ own control; therefore the antilog of the mean log time was expressed as a pef centage of the mean of the five antilogs for his five visits.
The results for the two groups were then averaged separately to give the figures ir Table II. There is little difference in the results for group A and group B, but there is ^ inprovement of about 20 per cent from visit one to visit five, which is presumably due to the effects of practice. In group B only one subject showed a lower score during the chlorpropamide period than during the control period. In case tests of unaffected limbs were diluting the effect of chlorpropamide, the results were analysed again and only counted if one of the limbs involved in the parti' cular test had achieved a clinical score for rigidity of 2 on more than one occasion' It was found that rigidity correlated better w ith time to complete the tests than di^ tremor. The results were substantially the same.
It was found that in most cases draughtsmanship improved from visit one to visi* five, so that the sheet for the latter usually scored 1. Averaging the scores for each group including left and right hand results together gave the results in Table III* Again the improvement due to chlorpropamide, if any, is less than that attributable to practice.

TABLE III
Tests of drawing and writing. The figures represent the average score at each visit, the possible range being from 1 to 5. There is a steady improvement from visit 1 to visit 5 in each group. 3-The total scores for eight patients in each group for rigidity and tremor are set at^H r^a^>^e ^ ^or eac^ ?* t^ie ^ast f?ur visits (some of the patients were not tested the first visit) _ There is a wide variation in the results during the control periods ^ght be expected with clinical assessment. However, there is no consistent pattern ^provement attributable to chlorpropamide. In particular, the improvement in remor in group A is not reflected in group B. ^ is difficult to devise tests which give useful information about the degree of limitan in Parkinson's disease, because it varies from time to time, particularly with j vPtl0n> and because rigidity, tremor and slowness also vary independently and affect tterent muscle groups in different patients. In this trial emotional factors were uced by making it double-blind, and variation between patients was reduced by ?ssing over. The tests were based on those used at the Frenchay Hospital neurorgical unit for assessing cases before and after operations on the basal ganglia, with 0j.e edification that time rather than subjective impression was used as the measure Performance when possible. jt benefit from chlorpropamide in the dose used (100 mg./day) was demonstrated. ?Wever, the results also suggest that after very few repetitions of complicated actions be6re be a considerable improvement in performance due to practice, and it may that tests using simpler actions such as some of those described by Dejong and Urns (1962) would have allowed smaller effects due to chlorpropamide to show up. r results make it unlikely that such effects would be large enough to be clinically Useful. SUMMARY A double-blind crossover trial of chlorpropamide 100 mg./day in addition to their ual drugs in eighteen patients with Parkinson's disease is reported. Chlorpropamide n?t prove better than the dummy as judged subjectively, by timed tests, or by its ect on rigidity and tremor.